Mixing devices for sample recovery from a USP induction port or a pre-separator

ABSTRACT

A mixer supports a cradle holding an inlet component for a cascade impactor, and has sealing caps to close open ends of the component to trap a solvent in the component. The cradle is rotated by a motor for dissolving particles in the inlet component.

BACKGROUND OF THE INVENTION

[0001] Two mixers are disclosed which are used for agitating solvents incomponents of dry powder inhalers to recover particles of internalclinging to wall of such components. The mixers are designed to assistlaboratory personnel in the measurement of the size distribution ofparticulate matter emitted from metered-dose, dry-powder, and similarinhalers. Such inhalers are in common use for the treatment of asthmatoday and are increasingly important in the therapeutic delivery ofpharmaceutical products of biotechnology.

[0002] Inhalers must be tested regularly both during laboratorydevelopment of new products and for quality control and assurance forcommercially sold products. The testing includes the measurement of thesize distribution of particles emitted by the inhalers. The UnitedStates Pharmacopeia (USP) and similar British, European, and Japaneseregulatory documents describe the use of cascade impaction devices asthe acceptable method for measuring size distribution. Further, theseinternational compendia describe the inlet that must be used tointroduce the particles into the cascade impactor. This inlet is knowncommonly as the USP Induction Port and is shown on page 1902 of USP 24,Section 601.

[0003] Because particulate matter accumulates in this induction portduring each test of an inhaler device, the laboratory analyst doing thetesting must quantify the mass of active drug material deposited in theinduction port. Typically, this procedure involves washing the insidewalls of the induction port with a solvent known to dissolve the activedrug ingredient and in some manner insuring that all drug material isrecovered from the inside walls of the induction port. The wash solventis then analyzed, typically by high-performance liquid chromatography(HPLC), to quantify the drug material.

[0004] The procedure of removing the drug material from the walls of theinduction port is typically an ad hoc one with no assurance that allmaterial is recovered. Further, the complete washing of the walls canconsume a minimum of 50 ml of solvent and up to 200 ml of solvent.Consequently, the active drug compound is diluted with solvent, and theanalysis via HPLC is relatively insensitive to the presence of the drugmaterial, compromising the accuracy of the overall test.

[0005] In addition, pre-separators are used in many impactors.Dry-powder inhalers typically contain large diluent particles along withthe active drug material. These diluent particles would interfere withthe functioning of the cascade impactor designed to recover the dryparticles allowed to enter the impactor during a test. Consequently,when an analyst tests a DPI, a pre-separator is attached to the inlet ofthe cascade impactor. Some drug material accumulates in thispre-separator during testing, and the active drug material captured inthe pre-separator must be quantified. This procedure requires washingwith a known amount of solvent, typically 50 ml to 200 ml in prior artprocedures, and/or shaking the device.

SUMMARY OF THE INVENTION

[0006] The present invention relates to mixing devices that allow a userto add a minimum amount of solvent to parts that have recesses andbends, and to mix the solvent, while unattended, with the active drugmaterial that has been clinging to the walls. This will thoroughly washthe walls, and cause the active drug material to be dissolved in thesolvent. The handling of the solvent to recover the material of interestafter this washing process is according to standards.

[0007] The mixing devices of the present invention include fixtures thatwill hold the induction port, on the one hand, and a pre-separator onthe other, and will rotate these components with the solvent containedin the chambers or passageways, after capping or sealing the openings,so the solvent acts on the material clinging to the interior surfaces.

[0008] The mixing devices insure that all of the surface areas arecontacted by the solvent during the mixing process, so that it is knownthat all of the active drug material has been dissolved and is availablefor analysis.

[0009] The mixing devices are made so that they will permit use of aminimum amount of the solvent, and will yet provide adequate mixing toinsure that all of the active drug materials are released.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010]FIG. 1 is a side elevational view of a mixing device utilized witha USP Induction Port;

[0011]FIG. 2 is a first end elevational view thereof;

[0012]FIG. 3 is a second end elevational view thereof;

[0013]FIG. 4 is a side elevational view of a second mixing deviceadapted specifically for a pre-separator, for holding it in place foragitation;

[0014]FIG. 5 is a side elevational view showing the mixing stand inposition; and

[0015]FIG. 6 is a schematic sectional view taken on line 6-6 in FIG. 4.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Referring to FIG. 1, a stand or frame 10 is used as a frame forthe mixing device indicated generally at 12. The stand has a base 14,and a pair of upright end members 16 and 18. The upright end memberssupport bearings 20A and 20B, that in turn rotatably mount shaftportions 22A and 22B that are used for supporting a cradle 24. Thecradle 24 has a base 26, and end supports 28 and 30 fixed to the baseend supports, as shown, have bent wall portions 28A and 30A that areformed at a substantially 450 to the main portions of the end supports.These bent wall portions have threaded openings to support threaded rods32A and 32B. The threaded rods have handles 34A and 34B for rotatingthem manually, and in addition, each of the rods 32A and 32B holds a capor cup structure 36A and 36B which are on the inner sides of the bentwall portions 28A and 30A, and are positioned between the end supports28 and 30.

[0017] A USP Induction Port is indicated at 40, and it has two tubularsections 42 and 44, at right angles to each other in a fixed assembly.The tubular sections 42 and 44 have standard open end connections orcouplings shown at 42A and 44A. The tubular sections form a passagewaythrough the interiors. In order to support the induction port 40 in thecradle 24, the screws 32A and 32B are backed out, so that the cupmembers 36A and 36B will permit the USP Inlet Port to slip into place,and then the screws are threaded down so that the cup members 36A and36B cover the open ends of the couplings 42A and 44A. Prior to puttingthe inlet in position, and closing it off, a suitable amount of solventis added to the interior chamber.

[0018] The cradle is then rotatably driven, by driving it with a motor46 that can be operated through a computer control 48 as to the timing,speed, and the amount of rotation. Pneumatic motors could be used, but astepper motor is shown as an exemplary embodiment.

[0019] The USP inlet will rotate around, and the solvent that isretained inside the tube will flow back and forth as the unit isrotated, and will contact all of the interior surfaces of the tubularsections 42 and 44.

[0020] In operation, the USP Inlet 40 is charged with a minimum amountof solvent, generally approximately 10 ml to 20 ml, and then the unit isput into place and the screws 32A and 32B are threaded so the caps 36Aand 36B hold the inlet between the caps and seal the end openings.

[0021] The entire inlet and cradle assembly then is rotated, and thesolvent will slosh or flow back and forth between both ends and thecenter portion 50 of the inlet, to insure adequate passage of thesolvent over the surfaces to dissolve the particles of the active drugmaterial.

[0022] Because the rotation is done by machine, the user not only savestime, because he can be at other tasks during the time that it is beingused, but he avoids the tedium of having to shake the inlet port himselfand to look into it to see if all the drug material has been recovered.Typically, the device can be rotated continuously or in one direction,or can be moved back and forth about the axis of the shafts 22A and 22B.

[0023] A second mixer is shown in FIGS. 4 through 6, and in thisinstance, a pre-separator assembly 60 is being cleaned. It has aninterior chamber, shown fragmentarily at 62, an inlet 64, and an outlettube 66. In some of these pre-separators, there is an impaction plate inthe center portions that is shown schematically at 68, but in any eventthe use is with the flow of an aerosol through the inlet 64, and theinterior chamber 62 to the outlet 66.

[0024] The fixture of the present invention includes a frame 69 that hasa base 69A supporting upright members 70A and 70B, that in turnrotatably mount a cradle 72. The cradle 72 has shafts 74A and 74B thatare rotatably mounted on suitable bearings on the upright members 70Aand 70B of the frame 69.

[0025] The cradle 72 has a lower support cross member 76, and an uppercross member 78 joining side members 77A and 77B. These cross memberssupport hold cups for holding the pre-separator 60. The lower crossmember 76 has an upwardly facing cup 80 that will receive the end of theoutlet 66, as shown. This cup 80 is supported on the cross member 76 andhas a shaft 81 that rotates in a bearing in the cross member 76. Aturnstile drive member 82 is driven by the lower end of shaft 81 thathas four arms that protrude at 90° to each other. Two of the arms 82Aand 82B are shown in FIG. 4, and two of the arms 82C and 82D are shownin FIG. 5. The cup 80 is rotatably mounted in the bearing 84 so that thecup will freely rotate.

[0026] An upright post 86 is fixed to the lower frame member 68A andextends upwardly. This post 68 acts as a turnstile, as will beexplained.

[0027] The upper cross member 78 rotatably supports a screw threadedshaft 88 that threads through a nut 89 that is mounted in a bearing 90so the screw threaded shaft can rotate and also can be threadablyadjusted. In other words, the bearing hub will permit the nut and shaftto rotate, but the screw threaded shaft 88 can be threaded, to move thecap shown at 92 vertically toward and away from the pre-separatorhousing 60.

[0028] In use, the device can be driven with a suitable motor 96 that isdriven from a computer 98 in a normal manner. This too can be a steppermotor or could be a pneumatic rotary actuator as desired. It also couldbe a reversible DC motor.

[0029] The screw threaded shaft 88 has a manual handle 88A, can bethreaded toward and away from the cross member 78.

[0030] When the pre-separator 60 is to be cleaned with a solvent, it isplaced with the outlet 66 in the lower cup 80, and then solvent is putinto the inlet 64, again using a limited amount of the solvent, probablyin the range of 30-40 ml. Then the cup 92 is lowered into position tohold the pre-separator in a sealed position. Suitable gasketingmaterials can be used in the cups in this form of the invention, as wellas the other form of the invention, to insure no leakage.

[0031] Once the pre-separator 60 is held between the cups 80 and 92, themotor 96 can be started and the unit can be rotated 360° about theshafts 74A and 74B. As it rotates, the post 84 will engage one of thearms 82A-82D and will rotate the pre-separator 60 about the uprightaxis, that is indicated at 100.

[0032] In this way, the pre-separator is indexed 90° about the uprightaxis for each revolution about the horizontal axis. If desired thepre-separator can be rotated a selected number of degrees and thenrotated in a reverse direction for proper use of the solvent indissolving the drug particles of interest.

[0033] The rotation about the vertical axis caused by the turnstile typepost and cross member, insures that there are no dead zones inside thepre-separator that remain unwashed or untouched by the solvent. The usercan also reverse the direction of the rotation about the horizontal axisto effect complete mixing.

[0034] The mixing devices shown improve the repeatability and uniformityof the sample recovery process from the pre-separator and from the USPInduction Port.

[0035] Although the present invention has been described with referenceto preferred embodiments, workers skilled in the art will recognize thatchanges may be made in form and detail without departing from the spiritand scope of the invention.

What is claimed is:
 1. A mixer device for an inlet component for aparticle impactor, wherein particles may cling to surfaces of aninterior component of the component, comprising a rotatable cradlesupporting the component, and a drive to rotate the cradle a desiredamount about an axis.
 2. The mixer device of claim 1, wherein the inletcomponent has at least one open end to receive a solvent, and the cradlehas an adjustable cap to overlie and close the open end.
 3. The mixerdevice of claim 1, wherein the inlet component has two open ends, and apair of adjustable caps on the cradle to overlie and close the openends, the caps comprising supports for supporting the inlet component onthe cradle.